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  • 1
    Online Resource
    Online Resource
    IL-27 and TCR Stimulation Promote T Cell Expression of Multiple Inhibitory Receptors
    The American Association of Immunologists ; 2019
    In:  ImmunoHorizons Vol. 3, No. 1 ( 2019-01-01), p. 13-25
    Details
    In: ImmunoHorizons, The American Association of Immunologists, Vol. 3, No. 1 ( 2019-01-01), p. 13-25
    Abstract: Inhibitory receptors (IR) are a diverse group of cell surface molecules that modulate T cell activation, but there are gaps in our knowledge of the cell-extrinsic factors that regulate their expression. The present study found that in vivo overexpression of IL-27 in mice led to increased T cell expression of PD-L1, LAG-3, TIGIT, and TIM-3. In vitro, TCR stimulation alone promoted expression of multiple IRs, whereas IL-27 alone induced expression of PD-L1. However, the combination of intermediate TCR stimulation and IL-27 resulted in synergistic induction of LAG-3, CTLA-4, and TIGIT. In vivo, infection with Toxoplasma gondii resulted in parasite-specific effector T cells that expressed high levels of IR, and at local sites of infection where IL-27 production was highest, IL-27 was required for maximal effector cell expression of PD-L1, LAG-3, CTLA-4, and TIGIT. Together, these results affirm the critical role of TCR signals in the induction of IR expression but find that during infection, IL-27 promotes T cell expression of IR.
    Type of Medium: Online Resource
    ISSN: 2573-7732
    URL: Article
    DOI: 10.4049/immunohorizons.1800083
    Language: English
    Publisher: The American Association of Immunologists
    Publication Date: 2019
    detail.hit.zdb_id: 2882729-6
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  • 2
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    Abstract 99: Single Cell RNA-Sequencing Reveals Array Of Immune Activation States In Intracerebral Hemorrhage
    Ovid Technologies (Wolters Kluwer Health) ; 2022
    In:  Stroke Vol. 53, No. Suppl_1 ( 2022-02)
    Details
    In: Stroke, Ovid Technologies (Wolters Kluwer Health), Vol. 53, No. Suppl_1 ( 2022-02)
    Abstract: Introduction: Secondary inflammation is a well-established cause of injury in intracerebral hemorrhage (ICH). One potential treatment for ICH limits inflammation through targeted metabolic modulation of immune cells, but leukocyte activation states in ICH are poorly defined. Using single-cell RNA sequencing (scRNA-seq) of patient hematoma evacuates, we characterized the inflammatory and metabolic profile of over a dozen identifiable leukocyte populations. This research provides insight into the dynamics of immune activation in ICH. Methods: Evacuated hematoma and peripheral blood samples from 8 ICH patients (62 ± 2.1 years) were collected via minimally invasive surgery (n=5) or craniotomy (n=3) (Fig. 1a). Collection time ranged from 0 to 4 days after ICH onset (1.5 ± 0.5 days). scRNA-seq was done on the 10X Genomics platform and analyzed using Seurat. Human monocyte-derived macrophage cultures were stimulated with S100A9 and IL-1β, two ICH-relevant inflammatory molecules, or LPS. Echinomycin and 2-deoxy-D-glucose were used to inhibit HIF signaling and glycolysis respectively. Results: Clustering revealed over a dozen transcriptionally distinct CNS-resident and immune cell types, many of which have little prior study in ICH (Fig. 1b). 3,395 differentially expressed genes between hematoma and peripheral blood (p 〈 0.05) were found in CD14 + monocytes and 932 in CD4 + effector T cells. Pathway analysis found upregulation of HIF signaling, glycolysis, and correlated networks of cytokine expression in the hematoma. The findings were significant across all immune populations but most prominent in myeloid cells (Fig. 1c). Inhibition of HIF and glycolysis in human macrophages in-vitro abrogated inflammatory and reparative cytokine production following inflammatory stimulation. In conclusion, this work highlights the interplay of inflammation and metabolism at a single cell level in ICH, contributing to knowledge of the immune response to brain injury.
    Type of Medium: Online Resource
    ISSN: 0039-2499 , 1524-4628
    URL: Article
    DOI: 10.1161/str.53.suppl_1.99
    RVK:
    XA 10000
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2022
    detail.hit.zdb_id: 1467823-8
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  • 3
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    Online Resource
    Leukocyte dynamics after intracerebral hemorrhage in a living patient reveal rapid adaptations to tissue milieu
    American Society for Clinical Investigation ; 2021
    In:  JCI Insight Vol. 6, No. 6 ( 2021-3-22)
    Details
    In: JCI Insight, American Society for Clinical Investigation, Vol. 6, No. 6 ( 2021-3-22)
    Type of Medium: Online Resource
    ISSN: 2379-3708
    URL: Article
    URL: Article
    DOI: 10.1172/jci.insight.145857
    DOI: 10.1172/jci.insight.145857DS1
    Language: English
    Publisher: American Society for Clinical Investigation
    Publication Date: 2021
    detail.hit.zdb_id: 2874757-4
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  • 4
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    Divergent Functions of Tissue-Resident and Blood-Derived Macrophages in the Hemorrhagic Brain
    Ovid Technologies (Wolters Kluwer Health) ; 2021
    In:  Stroke Vol. 52, No. 5 ( 2021-05), p. 1798-1808
    Details
    In: Stroke, Ovid Technologies (Wolters Kluwer Health), Vol. 52, No. 5 ( 2021-05), p. 1798-1808
    Abstract: Brain tissue-resident microglia and monocyte-derived macrophages (MDMs) are innate immune cells that contribute to the inflammatory response, phagocytosis of debris, and tissue repair after injury. We have previously reported that both microglia and MDMs transition from proinflammatory to reparative phenotypes over days after an intracerebral hemorrhage (ICH). However, their individual functional properties in the brain remain largely unknown. Here we characterized the differences between microglia and MDMs and further elucidate their distinct activation states and functional contributions to the pathophysiology and recovery after ICH. Methods: Autologous blood injection was used to model ICH in mice. Longitudinal transcriptomic analyses on isolated microglia and MDMs from mice at days 1, 3, 7 and 10 after ICH and naive controls identified core transcriptional programs that distinguish these cells. Imaging flow cytometry and in vivo phagocytosis assays were used to study phagocytic ability of microglia and MDMs. Antigen presentation was evaluated by ovalbumin-OTII CD4 T-cell proliferation assays with bone marrow–derived macrophages and primary microglia cultures. Results: MDMs had higher phagocytic activity and higher erythrophagocytosis in the ICH brain. Differential gene expression revealed distinct transcriptional signatures in the MDMs and microglia after ICH. MDMs had higher expression of MHCII (major histocompatibility complex class II) genes than microglia at all time points and greater ability to induce antigen-specific T-cell proliferation. Conclusions: The different ontogeny of microglia and MDMs lead to divergent responses and functions in the inflamed brain as these 2 cell populations differ in phagocytic functions and antigen-presenting capabilities in the brain after ICH.
    Type of Medium: Online Resource
    ISSN: 0039-2499 , 1524-4628
    URL: Article
    DOI: 10.1161/STROKEAHA.120.032196
    RVK:
    XA 10000
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2021
    detail.hit.zdb_id: 1467823-8
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  • 5
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    Online Resource
    Abstract TP239: Cholesterol And LXR Signaling In The Macrophage Response To Intracerebral Hemorrhage-relevant Stimulation
    Ovid Technologies (Wolters Kluwer Health) ; 2022
    In:  Stroke Vol. 53, No. Suppl_1 ( 2022-02)
    Details
    In: Stroke, Ovid Technologies (Wolters Kluwer Health), Vol. 53, No. Suppl_1 ( 2022-02)
    Abstract: Introduction: In the acute phase of intracerebral hemorrhage (ICH), blood-derived macrophages contribute to an inflammatory response that increases neuronal death and worsens patient outcome. A better understanding of the endogenous signals that control this response would aid in development of therapeutics to suppress it. Uptake of free cholesterol limits the macrophage response to microbial ligands, in part through activation of the transcription factor LXR. During ICH, blood-derived macrophages in the hematoma are not exposed to microbes but are exposed to the endogenous inflammatory molecule S100A9 as well as cholesterol in the form of myelin and cell debris. Methods and Results: Murine bone marrow-derived macrophages were treated with cholesterol before stimulation with S100A9 or LPS, which are both TLR4 ligands. The inflammatory response was measured by production of the cytokines/chemokines TNF, IL-6, CCL2, and IL-10 by multiplex ELISA and/or qPCR at 3 and 6 hours after stimulation. Activation of LXR was measured by expression of the LXR target genes Abca1 and Abcg1 by qPCR. Cholesterol limited inflammatory cytokine production in response to LPS but not to S100A9. Treatment with the LXR agonist T0901317 activated Abca1 and Abcg1 more strongly than cholesterol but was not as effective at suppressing cytokine production. Treatment with the LXR antagonist GSK2033 suppressed cholesterol-mediated expression of Abca1 and Abcg1 but did not block all suppressive effects of cholesterol on cytokine production. Conclusions: Cholesterol limits the macrophage response to LPS. This is partially through activation of LXR, but LXR-independent mechanisms are involved as well. Cholesterol does not limit the initial inflammatory response to the ICH-relevant molecule S100A9, which may help explain the robust acute inflammatory response that develops during acute ICH in the presence of abundant cholesterol.
    Type of Medium: Online Resource
    ISSN: 0039-2499 , 1524-4628
    URL: Article
    DOI: 10.1161/str.53.suppl_1.TP239
    RVK:
    XA 10000
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2022
    detail.hit.zdb_id: 1467823-8
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  • 6
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    Abstract 178: Cholesterol Limits Macrophage Activation in Response to Intracerebral Hemorrhage-Relevant Signals
    Ovid Technologies (Wolters Kluwer Health) ; 2020
    In:  Stroke Vol. 51, No. Suppl_1 ( 2020-02)
    Details
    In: Stroke, Ovid Technologies (Wolters Kluwer Health), Vol. 51, No. Suppl_1 ( 2020-02)
    Abstract: Introduction: In response to intracerebral hemorrhage (ICH), monocytes are recruited to the brain parenchyma, where they differentiate into macrophages and contribute to a pathological inflammatory response. However, by day 3 after ICH, brain macrophages have adopted a more reparative phenotype and are important for clearance of apoptotic cells and recovery. The signals that control this inflammatory to reparative differentiation are incompletely understood, but cholesterol has been found to limit macrophage activation in multiple systems. The brain has the highest cholesterol content of any organ and we hypothesized that cholesterol uptake by macrophages limits inflammation and promotes the development of reparative macrophages following ICH. Methods and Results: Murine bone marrow-derived macrophages were stimulated with a cocktail of thrombin, S100A8, and IL-1b in order to mimic the Danger-Associated Molecular Patterns present in the brain after ICH (ICH-DAMP), LPS, or vehicle for 14-18 hours. Cytokine production was quantified by cytometric bead array and activation markers by flow cytometry. ICH-DAMP was found to upregulate CCL2, IL-6 and TNF, recapitulating the inflammatory phenotype seen in the first days after ICH. However, when cells were stimulated in the presence of cholesterol, production of CCL2, IL-6, and TNF were limited. Dectin-1 has inhibitory properties in some sterile injury models. ICH-DAMP was found to limit expression of dectin-1, and cholesterol reversed this inhibition. Exposure to exogenous cholesterol also upregulated the cholesterol transporter ABCA1, allowing cells to efflux excess cholesterol. The drug Valspodar was therefore used to block cholesterol efflux and was found to further limit ICH-DAMP-mediated upregulation of CCL2. Conclusion: These results suggest that the cholesterol in the brain may limit macrophage activation in response to the stimuli present during intracerebral hemorrhage.
    Type of Medium: Online Resource
    ISSN: 0039-2499 , 1524-4628
    URL: Article
    DOI: 10.1161/str.51.suppl_1.178
    RVK:
    XA 10000
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2020
    detail.hit.zdb_id: 1467823-8
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  • 7
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    A phenotypically and functionally distinct human T H 2 cell subpopulation is associated with allergic disorders
    American Association for the Advancement of Science (AAAS) ; 2017
    In:  Science Translational Medicine Vol. 9, No. 401 ( 2017-08-02)
    Details
    In: Science Translational Medicine, American Association for the Advancement of Science (AAAS), Vol. 9, No. 401 ( 2017-08-02)
    Abstract: Allergen-specific type 2 helper T (T H 2) cells play a central role in initiating and orchestrating the allergic and asthmatic inflammatory response pathways. One major factor limiting the use of such atopic disease–causing T cells as both therapeutic targets and clinically useful biomarkers is the lack of an accepted methodology to identify and differentiate these cells from overall nonpathogenic T H 2 cell types. We have described a subset of human memory T H 2 cells confined to atopic individuals that includes all allergen-specific T H 2 cells. These cells are terminally differentiated CD4 + T cells (CD27 − and CD45RB − ) characterized by coexpression of CRT H 2, CD49d, and CD161 and exhibit numerous functional attributes distinct from conventional T H 2 cells. Hence, we have denoted these cells with this stable allergic disease–related phenotype as the T H 2A cell subset. Transcriptome analysis further revealed a distinct pathway in the initiation of pathogenic responses to allergen, and elimination of these cells is indicative of clinical responses induced by immunotherapy. Together, these findings identify a human T H 2 cell signature in allergic diseases that could be used for response-monitoring and designing appropriate immunomodulatory strategies.
    Type of Medium: Online Resource
    ISSN: 1946-6234 , 1946-6242
    URL: Article
    DOI: 10.1126/scitranslmed.aam9171
    Language: English
    Publisher: American Association for the Advancement of Science (AAAS)
    Publication Date: 2017
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  • 8
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    Online Resource
    PD-L1–PD-1 interactions limit effector regulatory T cell populations at homeostasis and during infection
    Springer Science and Business Media LLC ; 2022
    In:  Nature Immunology Vol. 23, No. 5 ( 2022-05), p. 743-756
    Details
    In: Nature Immunology, Springer Science and Business Media LLC, Vol. 23, No. 5 ( 2022-05), p. 743-756
    Type of Medium: Online Resource
    ISSN: 1529-2908 , 1529-2916
    URL: Article
    DOI: 10.1038/s41590-022-01170-w
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2022
    detail.hit.zdb_id: 2026412-4
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  • 9
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    Online Resource
    Role of Inflammatory Processes in Hemorrhagic Stroke
    Ovid Technologies (Wolters Kluwer Health) ; 2023
    In:  Stroke Vol. 54, No. 2 ( 2023-02), p. 605-619
    Details
    In: Stroke, Ovid Technologies (Wolters Kluwer Health), Vol. 54, No. 2 ( 2023-02), p. 605-619
    Abstract: Hemorrhagic stroke is the deadliest form of stroke and includes the subtypes of intracerebral hemorrhage and subarachnoid hemorrhage. A common cause of hemorrhagic stroke in older individuals is cerebral amyloid angiopathy. Intracerebral hemorrhage and subarachnoid hemorrhage both lead to the rapid collection of blood in the central nervous system and generate inflammatory immune responses that involve both brain resident and infiltrating immune cells. These responses are complex and can contribute to both tissue recovery and tissue injury. Despite the interconnectedness of these major subtypes of hemorrhagic stroke, few reviews have discussed them collectively. The present review provides an update on inflammatory processes that occur in response to intracerebral hemorrhage and subarachnoid hemorrhage, and the role of inflammation in the pathophysiology of cerebral amyloid angiopathy–related hemorrhage. The goal is to highlight inflammatory processes that underlie disease pathology and recovery. We aim to discuss recent advances in our understanding of these conditions and identify gaps in knowledge with the potential to develop effective therapeutic strategies.
    Type of Medium: Online Resource
    ISSN: 0039-2499 , 1524-4628
    URL: Article
    DOI: 10.1161/STROKEAHA.122.037155
    RVK:
    XA 10000
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2023
    detail.hit.zdb_id: 1467823-8
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  • 10
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    Abstract TP216: Suppression Of Macrophage Activation By Myelin
    Ovid Technologies (Wolters Kluwer Health) ; 2023
    In:  Stroke Vol. 54, No. Suppl_1 ( 2023-02)
    Details
    In: Stroke, Ovid Technologies (Wolters Kluwer Health), Vol. 54, No. Suppl_1 ( 2023-02)
    Abstract: Introduction: In intracerebral hemorrhage, blood-derived macrophages contribute to a neurotoxic inflammatory response. The endogenous signals that are able to suppress this response are poorly understood. Macrophages likely phagocytose myelin in the CNS during intracerebral hemorrhage and uptake of myelin limits macrophage cytokine production in response to LPS. The components of myelin responsible for its suppressive effects are not well understood, although cholesterol is a likely candidate. Additionally, the broader effects of myelin on macrophage phenotype have not been investigated. Methods and Results: Murine bone marrow-derived macrophages were treated with cholesterol before stimulation with S100A9 or LPS. The inflammatory response was measured by production of TNF, IL-6, CCL2, and IL-10 by ELISA. Cholesterol limited inflammatory cytokine production in response to LPS but not to S100A9. The LXR antagonist GSK2033 partially blocked the suppressive effects of cholesterol but activation of LXR with T0901317 was not sufficient to suppress cytokine production. An RNA-Seq screen was performed to examine broader effects of myelin and cholesterol uptake. BMDMs were pretreated with cholesterol, myelin, or the LXR agonist T0901317 before stimulation with S100A9, LPS, TNF, IFNg, IL-4, IL-10, TGFb, Poly(I:C), or Pam3CSK4. Myelin suppressed responses to all of these stimulations, as did T0901317 but to a lesser extent. Cholesterol suppressed the macrophage response to LPS but not the other stimulations. Conclusions: Myelin broadly limits macrophage responses to pro-inflammatory signals. Cholesterol alone limits the response to LPS, partially through activation of LXR, but LXR-independent mechanisms appear to be involved as well. Cholesterol does not limit the response to other stimulations, suggesting that other components of myelin or activation of phagocytic receptors contribute to suppression of the macrophage response.
    Type of Medium: Online Resource
    ISSN: 0039-2499 , 1524-4628
    URL: Article
    DOI: 10.1161/str.54.suppl_1.TP216
    RVK:
    XA 10000
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2023
    detail.hit.zdb_id: 1467823-8
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